Use of oxicam compounds

ABSTRACT

Methods of treating and/or preventing arteriosclerosis are disclosed. In certain methods, a composition containing at least one lornoxicam or lornoxicam analogue that inhibits cyclooxygenase 1 and cyclooxygenase 2 (COX 1 and COX 2), cannot cross the blood/brain barrier under physiological conditions, and reduces the prostaglandin E2-induced induction of the amyloid precursor protein (APP) is administered to a subject to treat and/or prevent arteriosclerosis in the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 10/558,117filed on Mar. 2, 2007, which is a U.S. national phase application under35 U.S.C. § 371 of International Application No. PCT/AT04/00185 filedMay 27, 2004, which claims priority to Austrian Application No. A819/2003 filed May 27, 2003. The entire text of each of theabove-referenced disclosures is specifically incorporated by referenceherein without disclaimer.

BACKGROUND

The invention relates to the production of pharmaceutical compositionsfor the treatment of Alzheimer's Disease and arteriosclerosis.

The etiology of Alzheimer's Disease (AD) has not yet been clarified.According to the “amyloid hypothesis” of AD, a change occurs in thecleavage of the amyloid precursor protein (APP). The so-called β-42peptide is deposited, whereby cerebral plaques form. Also as aconsequence of the resultant hypoperfusion, neuronal degenerationoccurs.

The treatment methods currently employed all comprise the administrationof cholinergic agents, in particular of inhibitors ofacetylcholinesterase, since AD involves substantial losses ofcholinergic neurons, and acetylcholinesterase inhibitors increase theacetylcholin level, so that the remaining neurons remain activated(“firing”). However, the progressive loss of neurons unfortunatelycannot be stopped by this treatment.

Further target molecules, the influencing of which is currently beingdiscussed and tested in the context of an AD therapy, aresecretase-modulating substances, in particular β- and γ-secretaseinhibitors, inhibitors of cholesterol biosynthesis, inhibitors ofamyloid aggregation, immunological methods, in particular with the A-βpeptide or antibodies against this peptide, prevention of the APPexpression, increase of the APP clearance, modulation of thephosphorylation of tau protein and lowering of the serum amyloid P level(Wolfe, Nat. Rev. Drug Discov. 1 (2002) 859-866).

In US 2002/0052407 A1, U.S. Pat. No. 6,187,756 B1 and U.S. Pat. No.6,184,248 B1, substance mixtures are disclosed which containnon-steroidal anti-inflammatory drugs (NSAID) for inhibiting an abnormalexpression of the amyloid precursor protein (APP) which is known to beinvolved in Alzheimer's Disease. By means of in vitro and in vivo testsit could be shown in the examples that the inventive substances inhibitthe over-expression of APP. All three documents suggest the use ofnon-steroidal anti-inflammatory drugs which only inhibitcyclooxygenase-2, yet not cyclooxygenase-1, for the prevention orpossible healing of Alzheimer's Disease.

Furthermore, in these documents cyclooxygenase-2 inhibitors exclusivelyare claimed. Oxicams and, in particular, lornoxicam or analogouscompounds are not disclosed therein.

In WO 93/24115 A1, a method for treating dementia, in particularAlzheimer's Disease, by administering non-steroidal anti-inflammatorydrugs has been described. Besides a number of other substances, alsooxicams, in particular piroxicam, isoxicam and sudoxicam have beensuggested, yet not lornoxicam or analogous compounds.

In WO 01/78721 A1, a method for the prevention and/or for the healing ofAlzheimer's Disease by administering substances that reduce the contentof the amyloid-β-polypeptide (Aβ) Aβ₄₂ is described. Since a highexpression rate of Aβ₄₂ is held responsible for the development ofAlzheimer's Disease, the course of the disease can be positivelyinfluenced by reducing this polypeptide. In this document, moreover, atest is described in which the influence of various NSAIDs on theexpression rates of two Aβ-polypeptides, Aβ₄₀ and Aβ₄₂, are shown. Fromthis it results that oxicams, in particular meloxicam, peroxicam,isoxicam and tenoxicam (lormoxicam or analogous compounds thereof arenot mentioned here) do not influence the expression of Aβ₄₂ and evenincrease the expression thereof, respectively. From this document,therefore, the person skilled in the art could derive that oxicams haveproven as not advantageous to be used for the reduction of Aβ₄₂.

From US 2002/0119193 A1, pharmaceutical compositions are apparent whichi.a. contain selective cyclooxygenase-2 inhibitors and are used for thetreatment of various diseases, among them Alzheimer's Disease. Accordingto this document, the inventive cyclooxygenase-2 inhibitors haveadvantages over the conventional, non-steroidal, anti-inflammatoryactive substances. Thus, also the teaching of this document leads awayfrom the use of oxicams which inhibit both cyclooxygenase-1 andcyclooxygenase-2.

None of the previously described concepts, however, has actually enableda breakthrough in the efficient treatment and, above all, in theprevention of AD. Therefore, medicinal treatment and prevention measuresfor AD are still urgently needed.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to the use of lornoxicam orlornoxicam analogues for producing a pharmaceutical composition for thetreatment or prevention of Alzheimer's Disease (AD) or ofarteriosclerosis.

Only recently it has been found that peripheral platelets are theprimary source of the β-42 peptide deposited in the cerebral plaques.With this finding, AD is to be defined as a vascular disease. The newetiological interpretation is supported by the results of clinicalstudies which show that non-steroidal anti-inflammatory drugs (NSAIDs)alleviate symptoms of AD. These studies in turn were based on thehypothesis that AD were an inflammatory disease of the brain, variouscauses for the inflammatory symptoms having been mentioned. Thus, byadministering from 100 to 150 mg of indometacin per day, the cognitivedegradation could be reduced by approximately 9% over 6 months.Likewise, it has been known that NSAIDs have an influence on APP proteinexpression and processing in that they reduce the prostaglandinE2-induced APP expression and at the same time cause changes in thecleavage of APP.

In studies with Ibuprofen and Indometacin it could be demonstrated thatthe portion of the amyloid β-42 peptide is lowered and that of thenon-amyloidogenic soluble APP is increased. From the fact that plateletsare a primary source of the proteins in amyloid plaques, there alsoresults a correlation to arteriosclerotic diseases.

Here, too, the NSAID-caused reduction of the APP expression inplatelets, the change in the cleavage of the platelet-APP with areduction of the plasma A-β and an increase in the non-amyloidogenicsoluble APP, the reduction of the amyloid plaques in the cerebralvessels and the reduced cerebrovascular hypoperfusion are the basicmechanisms of the therapeutic effect.

Therefore, the present invention is based on the idea that theunderlying cause of sporadic AD is a vascular disturbance and that theprimary source of the cerebrovascular deposition of β-42 are theperipheral platelets.

With the use according to the invention, the expression of APP inplatelets is selectively prevented, and the cleavage of platelet APP isinfluenced, wherein the plasma A-β level decreases and the level ofnon-amyloidogenic soluble APP increases. On account of the reducedplaque formation in the cerebral vessels, cerebrovascular hypoperfusiondoes not occur, whereby the neurodegeneration is reduced.

One of the essential pre-requisites for the use according to theinvention is that the inventive substance, i.e. lornoxicam or alornoxicam-analogue, inhibits both central isozymes of the eicosanoidmetabolism, i.e. COX-1 and COX-2. Particularly the fact that the isozymeCOX-2 is associated with inflammatory processes has supported theprevailing opinion which suggested the use of COX-2-selectivebrain-effective drugs. However, since according to the above-mentionednew findings peripheral platelets expressing COX-1 only are the primarysource of the plaque protein, according to the invention both inhibitingactivities must be provided in an efficient treatment and preventionagent.

Since in the brain COX-2 is also constitutively expressed, with a viewto the peripheral occurrence of the platelets, the brain-effectivenessof an active substance must be considered not only as undesirable, but,much rather, even as a disadvantage, since the inhibition of aconstitutively expressed enzyme as a rule causes the inhibition ofphysiological processes and, thus, may cause drug side effects. Thus,also the property of the agents to be used according to the invention ofnot crossing the blood-brain barrier is an important characteristicaccording to the invention.

The effectiveness of lornoxicam or of lornoxicam analogues within thescope of the present invention has also been surprising in view of theprior art, in particular in view of the findings provided in WO 01/78721A1, since the oxicams described there, in particular meloxicam,peroxicam, isoxicam and teroxicam, either could not influence theexpression of Aβ₄₂ or even increased them.

According to the present invention, however, lornoxicam and itsanalogues have proved extremely advantageous in the treatment and, aboveall, in the prevention or slowing down of AD and arteriosclerosis. By“lornoxicam analogues” within the scope of the present invention allsubstances are to be understood which—derived from the lornoxicamstructure—have the same basic effect in the peripheral platelets aslornoxicam or an effect comparable thereto with regard to Aβ-42, whichmeans that they

inhibit cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2),

cannot cross the blood/brain barrier under physiological conditions, and

reduce the prostaglandin E2-induced induction of the amyloid precursorprotein (APP).

Examples of such lornoxicam analogues are enolether of6-chloro-4-hydroxy-2-methyl-N-(2-pyridyl)-2H-thieno(2,3-e)-1,2-thiazine-3-carboxylicacid amide-1,1-dioxide (as described in EP 0 313 935 A1, and inparticular claimed by EP 0 313 935 B1),4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-6-trifluoromethyl-2H-thieno[2,3-e]-1,2thiozine-1,1-dioxide (as described in EP 0 103 142 A1 and in particular,claimed in EP 0 103 142 B1); thienothiazine derivatives according to EP0 001 113 A1 (B1) having the general formula I

wherein A together with the two carbon atoms of the thiazine ring formsthe group

and the broken line indicates the double bond present in the first andin the last instance, R¹ represents lower alkyl, R² represents2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl,5-methyl-1,3,4-thiadiazolyl, 2-pyrazinyl, 2-pyrimidinyl,1,2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl,4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl,4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl,3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl-4-pyrimidinyl,1,2,3,4-tetrazol-5-yl or a phenyl residue optionally substituted byhalogen, hydroxy, lower alkyl, trifluormethyl or lower alkoxy, and R³represents halogen, as well as salts thereof, wherein the term “loweralkyl” means straight-chain or branched saturated hydrocarbon groupswith 1-4 carbon atoms, such as, e.g., methyl, ethyl, propyl, isopropyland t-butyl; the term “lower alkoxy” relates to hydrocarbonoxy groupswith up to 4 C atoms, and the term “halogen” refers to the 4 halogenschlorine, bromine, fluorine, iodine; particularly preferably, R³represents chlorine or bromine, wherein chlorine is particularlypreferred; R¹ preferably represents the methyl group; R² preferablyrepresents 2-thiazolyl, 5-isoxazolyl or 2-pyridyl; A preferably is thegroup

further preferred are[3aα,8bα)]-1,2,3,3a,4,8b-hexahydropyrrolo[3′,2′:4,5]-cyclopenta[1,2-c]pyridinederivatives of the general formula

or [3aα,8bα)]-1,2,3,3a,4,8b-hexahydropyrrolo[2′,3′:3,4]-cyclopenta[1,2-b]pyridine-derivativesof the general formula

wherein:Z represents a single bond or CH₂,R1 represents hydrogen or a straight-chain or branched, optionallyunsaturated lower-alkyl residue which may also be perfluorinated,R2 and R3 independently represent hydrogen, a straight-chain orbranched, optionally unsaturated lower alkyl residue which may also beperfluorinated, lower-alkoxy, lower-alkyl-thio or halogen,as well as their optically pure antipodes and pharmaceutically usablesalts.

Compounds of the general formulas (II) and (III) can be produced byreductively converting a compound

wherein R2 and R3 are as defined above, into the compound of the generalformula II or III, wherein Z=single bond and R1=hydrogen, optionallyreacting it with enantiomerically pure 1-phenylethyl-isocyanate to thecompound of the general formula

recovering from the thus obtained diastereomeric mixture the lessreadily soluble diastereomer by crystallization, cleaving the thusobtained diastereomerically pure compound of the general formula (Va) or(Vb) under suitable conditions to the enantiomerically pure compound ofthe general formula (II) or (III), wherein Z=single bond andR1=hydrogen, optionally reacting it under alkylating conditions tocompounds of the general formula (II) or (III), wherein Z=CH₂, andoptionally converting the compound of the general formula (II) or (III)as well as its racemic mixture into its pharmaceutically usable salts,wherein the term “lower alkyl” means a straight-chain or branched alkylresidue with 1-4 carbon atoms, e.g. methyl, ethyl, n- and i-propyl, n-,i- and t-butyl; the term “lower alkoxy” means a straight-chain orbranched alkoxy residue with 1-4 carbon atoms, e.g. methoxy, ethoxy, n-and i-propoxy, n-, i- and t-butoxy; the term “lower-alkyl-thio” means astraight-chain or branched alkyl-thio residue with 1-4 carbon atoms,e.g. methyl-thio, ethyl-thio, n- and i-propyl-thio, n-, i- andt-butyl-thio; and the term “halogen” means fluorine, chlorine, bromineor iodine.

The reactions according to the invention are best carried out bydissolving the compound of the general formula (IVa) or (IVb) in a polarsolvent, such as, e.g., acetic acid ethyl ester, dioxane, ethanol ormethanol, admixing 1-5 equivalents of a suitable catalyst, such as,e.g., W2-Raney Nickel or Raney Cobalt and the like, and hydrogenating at40 to 70° C. up to a stoichiometric hydrogen uptake. For separation ofthe enantiomers, the thus obtained racemic compound of the generalformula (II) or (III), wherein Z=single bond and R1=hydrogen, can bereacted in an inert solvent, such as, e.g., tetrahydrofurane, dioxane oracetone, with 1 equivalent (+) or (−) 1-phenylethylisocyanate to obtaina compound of the general formula (Va) or (Vb), and from thediastereomeric mixture thus obtained, the less readily solublediastereomer can be recovered by crystallization. For cleavage the thusobtained diastereomerically pure compound of the general formula (Va) or(Vb) is dissolved in a high-boiling alcohol, such as, e.g., propanol,butanol, pentanol, glycol etc. or the aqueous mixtures thereof, andheated for 1-24 hours to boiling with 5-20 equivalents of a base, suchas sodium propanolate, -butanolate, -pentanolate or sodium hydroxide.The thus obtained enantiomerically pure compound of the general formula(II) or (III), wherein Z=single bond and R1=hydrogen, as well as itsracemic form, optionally is dissolved for alkylation in an inertsolvent, such as, e.g., tetrahydrofurane, dioxane, acetonitrile ordimethylformamide etc., admixed with 1-20 equivalents of the compound ofthe formula

R1-CHO  (VI),

wherein R1 is as defined above, and 1.5-4 equivalents of a reducingagent, such as, e.g., sodium cyanoborohydride or the like, and reactedat −20° C. to 100° C. for between 1 and 24 hours.

The compounds of the general formula (II) or (III) obtained in thisreaction are basic compounds and can be converted into theirpharmaceutically compatible salts in a conventional manner by means ofinorganic or organic acids. Salt formation can be effected e.g. bydissolving the compounds of the formula (II) or (III) in a suitablesolvent, e.g. water, a lower aliphatic alcohol, THF, dioxane, benzene,diethyl ether, DMF or DMSO, admixing an equivalent amount of the desiredacid, providing for a good mixing and withdrawing the solvent undervacuum when the salt formation has been completed. Optionally, the saltcan be re-crystallized after isolation.

Further preferred examples of the inventive lornoxicam analogues are thesubject matter of AT 400 567 B and of AT 400 437 B, in particular thesubstances described in claims 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ofAT 400 567 B and in claims 2, 3 or 4 of AT 400 437 B. Further lornoxicamanalogues preferred according to the present invention are disclosed inEP 0 657 459 A1, in particular the substances claimed in claims 2, 3 and4 thereof.

Pharmaceutically usable salts are those of strong inorganic acids, suchas, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid etc., butalso those of organic acids, such as, e.g., fumaric acid, citric acid,sebacic acid, etc.

Preferably, the administration of the substance should not entail anysevere undesired events, i.e. it should be free from side-effects. Bythis, the prophylactic intake of this substance for preventing AD orarteriosclerosis becomes possible without confronting the patient withundesired side reactions. A prophylactic treatment is primarilyindicated for those persons who have a high risk of AD orarteriosclerosis, be it by genetically caused circumstances (familialaccumulation of such diseases) or by other parameters. For defining thefreedom from side-effects according to the present invention, thedefinitions provided in relevant pharmaceutical textbooks and standardliterature can be resorted to. For example, the side-effects foundduring observation of usage should be below 1%, preferably below 0.5%,more preferably below 0.1%, in particular below 0.05%. Optionally, thesubstances according to the invention can be combined with furtherdrugs, particularly those which counteract possible negative effects,such as, e.g., gastric mucosa initiating properties, (e.g. antacids, H2receptor antagonists, proton pump inhibitors, . . . ). This must beconsidered primarily in case of long-term applications.

Besides lornoxicam, substances particularly preferred to be used withinthe scope of the present invention are primarily

-   6-chloro-4-(1-(ethoxycarbamoyloxy)-ethoxy)-2-methyl-N-(2-pyridyl)-2H-thieno-(2,3-e)-1,2-thiazine-3-carboxylic    acid amide-1,1-dioxide,-   6-chloro-4-hydroxy-2-methyl-3-(2-pyridyl-carbamoyl)-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide,-   (+)-[3aα,8bα)]-1,2,3,3a,4,8b-hexahydropyrrolo[2′,3′:3,4]cyclopenta[1,2-b]pyridine-dihydrochloride;-   (+)-[3aS-(3aα,8bα)]-1,2,3,3a,4,8b-hexahydropyrrolo-[3′,2′:4,5]cyclopenta[1,2-c]pyridine-dihydrochloride;-   (−)-[3aR-(3aα,8bα)]-1,2,3,3a,4,8b-hexahydropyrrolo-[3′,2′:4,5]-cyclopenta[1,2-c]pyridine-dihydrochloride;-   (−)-[3aα,8bα]-1,2,3,3a,4,8b-hexahydropyrrolo-[2′,3′:3,4]-cyclopenta[1,2-b]pyridine-dihydrochloride;-   (−)-[(3aα,8bα)]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo-[2′,3′:3,4]-cyclopenta[1,2-b]pyridine-dihydrochloride;-   (+)-[3aS-(3aα,8bα)]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo-[3′,2′:4,5]-cyclopenta[1,2-c]pyridine-dihydrochloride;-   (+)-[3aα,8bα]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo-[2′,3′:3,4]-cyclopenta[1,2-b]pyridine-dihydrochloride;-   (+)-[3aS-(3aα,8bα)]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo-[3′,2′:4,5]cyclopenta[1,2-c]pyridine-dihydrochloride.

The particular advantage according to the invention of the applicationof lornoxicam as well as of the lornoxicam analogues results from aparticularly advantageous combination of the pharmacodynamic andpharmacokinetic properties of this active substance.

According to the present invention, the pharmaco-dynamic particularitiesof lornoxicam or lornoxicam analogues causing the invention are thefollowing:

One particularly important property which causes the particularinventive suitability of lornoxicam resides in the fact that thesubstance inhibits both central isozymes of the eicosanoid metabolism,i.e. COX-1 and COX-2. The henceforth established fact that peripheralplatelets expressing COX-1 only, are the primary source of the plaqueprotein, is the reason for the superiority of the inventive applicationof lornoxicam and its analogues, respectively, which have a significantinhibition of COX-1.

Moreover, lornoxicam is an active substance with a particularly highintrinsic activity. Since a therapy for the prevention of AD and ofarteriosclerosis, respectively, must last over an extended period oftime, a reduced load of active substance on the body constitutes afurther advantage.

Furthermore, lornoxicam is not capable of crossing the blood-brainbarrier (Pruss et al., 3. Interscience World Conference on Inflammation,Monte Carlo (1989), Abstract 41).

In view of the extended duration of a preventive therapy of AD withlornoxicam, the short plasma half-life of lornoxicam is a specialadvantage since by this a cumulation in blood will not occur. Likewise,the known good gastro-intestinal and other tolerance of the activesubstance is of great importance. Thus, in one million of prescriptions,less than 10 severe undesired events have been reported, and theside-effects found during observation of usage have been far below 0.05%(wherein so far all the side effects could be repaired again).

The said combination of pharmaco-dynamic and pharmaco-kinetic propertiesof the active substance lornoxicam in a constellation which isparticularly favorable for the purpose of the therapy of AD and ofarteriosclerotic diseases is not found in any other hitherto knownsubstance in a comparable way.

The invention will be explained in more detail by way of the followingexamples as well as the drawing figures to which, however, it shall notbe restricted.

BRIEF DESCRIPTION OF THE DRAWINGS

Therein,

FIGS. 1, 2 and 3 show the arachidonic acid pathway and its correlationwith COX-1 and COX-2;

FIG. 4 shows the COX-inhibiting effect of some substances;

FIG. 5 shows the lornoxicam pharmaco-kinetics in healthy youngvolunteers after an oral single dose;

FIG. 6 shows the inhibition of COX-1-derived TXB2 from whole bloodduring coagulation by lornoxicam;

FIG. 7 shows the inhibition of the eicosanoid formation in HEL cells(COX-1) and LPS-stimulated Mono Mac 6-cells (COX-2) by lornoxicam.

DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS Examples Example 1Effect of Lornoxicam on APP Processing In Vitro and In Vivo

1.1. Characterization of a specific influence on APP cleavage in vitro:

-   -   1.1.1. Influence of lornoxicam on APP processing in neuronal        cell line (SH-SY5Y)        -   Release of the amyloid β-42 peptide (lowered by NSAIDs)        -   Release of the non-amyloid sAPPα protein (increased by            NSAIDS)        -   Expression of the APP holoprotein (lowered by NSAIDs)

1.2. Characterization of Human Thrombocytes as Peripheral Model for theEffect of Lornoxicam on Nerve Cells

In peripheral thrombocytes of patients suffering from Alzheimer'sDisease it has been demonstrated that the non-amyloid sAPPα protein isalso produced in a reduced amount (Colciaghi et al., Mol. Med. 8 (2002),67-74). The expression of the non-amyloid sAPPα can be increased innerve cells by NSAIDs (Avramovich et al., J. Biol. Chem. 277 (2002),31466-73). The results of these two studies lead to the expectation thatthe non-amyloid sAPPα protein is very well suited to peripherallyobserve the specific activity of lornoxicam.

1.2.1. Influence of Lornoxicam on APP-Processing in Human ThrombocytesIn Vitro

-   -   Release of non-amyloid sAPPα protein of activated thrombocytes

1.2.2. Influence of Lornoxicam on APP-Expression of Human Thrombocytesof Alzheimer's Disease Patients In Vivo Expression of APP-holoprotein

(This parameter is meaningful if lornoxicam does not have a specificinfluence on APP processing, since APP holoprotein is expressed inincreased amounts in the frontal cortex (Golde et al., Nueron 4 (1990),253-267) and NSAIDs can reduce its expression. In an ongoing study, alsoincreased APP holoprotein expression has been demonstrated onthrombocytes of Alzheimer patients).

-   -   APP ratio of the thrombocytes of Alzheimer's Disease patients        before and after treatment with lornoxicam.    -   Release of the non-amyloid sAPPα protein of activated        thrombocytes        These investigations are aimed at the in vivo-monitoring on        peripheral blood thrombocytes for the postulated effect of        lornoxicam on nerve cells.        2.2. Protein-Profiling (Proteomics) of Human Thrombocytes after        In Vivo Administration of Lornoxicam

Comparison of the thrombocyte proteome of Alzheimer's Disease andhealthy individuals before and after lornoxicam medication.

These investigations were aimed at the in vivo-protein profiling of theeffect of lornoxicam on human thrombocytes.

2.3. Influence of Lornoxicam on the Pharmacoproteomics of HumanThrombocytes In Vitro: Protein-Profiling (Proteomics) of HumanThrombocytes After In Vitro Incubation with Lornoxicam

Comparison of the thrombocyte proteome of lornoxicam-treatedthrombocytes with non-treated control thrombocytes.

This example is aimed at the characterization of the thrombocyteproteins which are directly affected by the cyclooxygenase-inhibitorlornoxicam.

1. A method of treating and/or preventing arteriosclerosis in a subjectcomprising: obtaining a composition comprising at least one lornoxicamor lornoxicam analogue that inhibits cyclooxygenase 1 and cyclooxygenase2 (COX 1 and COX 2), cannot cross the blood/brain barrier underphysiological conditions, and reduces the prostaglandin E2-inducedinduction of the amyloid precursor protein (APP); and administering thecomposition to a subject.
 2. The method of claim 1, wherein practice ofthe method results in undesired side effects in less than 1% ofsubjects.
 3. The method of claim 2, wherein practice of the methodresults in undesired side effects in less than 0.5% of subjects.
 4. Themethod of claim 3, wherein practice of the method results in undesiredside effects in less than 0.1% of subjects.
 5. The method of claim 4,wherein practice of the method results in undesired side effects in lessthan 0.05% of subjects.
 6. The method of claim 1, wherein thecomposition comprises a lornoxicam-analogue further defined as6-chloro-4-(1-(ethoxycarbamoyloxy)-ethoxy)-2-methyl-N-(2-pyridyl)-2H-thieno-(2,3-e)-1,2-thiazine-3-carboxylicacid amide-1,1-dioxide or6-chloro-4-hydroxy-2-methyl-3-(2-pyridyl-carbamoyl)-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide.7. The method of claim 1, wherein the subject is a human.